Essential tremor (ET) is the most common cause of tremor in humans yet its etiology remains unclear. Environmental toxicants may contribute to its etiology. Such factors are thought to play an important role in other neurodegenerative diseases, but their role in ET has received less attention. During the last 4 years (2000-2004), we studied 3 putative toxicants: lead, beta carboline alkaloids (BCAs; harmane and harmine) and organochlorine pesticides (OCRs) in 251 ET cases and 300 controls. Harmane and harmine were the neurotoxins of primary interest because the only experimental model for ET involves the administration of BCAs to laboratory animals. Our data indicates that blood concentrations of harmane and harmine are strongly associated with an increased risk of ET. Our overarching aim over the next 4 years is to carry our study of the BCAs forward. We plan to expand our sample to 900 subjects (450 ET cases and 450 matched controls). This proposed sample size is much larger than that used in other case-control studies (which have used 10-15 subjects in each group), and will provide a unique opportunity to test our hypotheses. In Aim 1, we will explore the mechanisms (in either cases or controls) that underlie a higher blood BCA concentration. Are higher blood BCA concentrations associated with genetic differences in ability to metabolize BCAs (i.e., polymorphisms in genes that are involved in BCA metabolism, CYP1A2 and N-acetyltransferase 2, Aim 1A)? Are higher blood harmane concentrations due to greater current dietary exposure, assessed with a meat questionnaire (Aim 1B)? Do genetic and dietary factors interact in their influences on blood harmane concentrations (Aim 1C)? In Aim 2, we will further explore the association between disease status (ET vs. controls) and these genetic and dietary factors. Is the risk of ET ultimately associated with these genetic factors (Aim 2A), dietary factors (Aim 2B), or the interaction of these factors (Aim 2C)? We hypothesize that dietary exposure and genetic polymorphisms will be associated both with blood BCA concentrations and with disease status. An environmental/toxic component to the etiology of ET may account for a significant proportion of the incidence of this disease in the population. Identification and understanding these toxicants is the first step in preventing a disease with only limited treatment options.